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Tracing the Origin of Glomerular Extracapillary Lesions from Parietal Epithelial Cells
Authors:Bart Smeets  Sandra Uhlig  Astrid Fuss  Fieke Mooren  Jack F.M. Wetzels  Jürgen Floege  Marcus J. Moeller
Affiliation:*Division of Nephrology and Immunology and ;Interdisciplinary Centre for Clinical Research “BIOMAT”, University Hospital of the Aachen University of Technology, Aachen, Germany; and ;Departments of Pathology and ;§Nephrology, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands
Abstract:Cellular lesions form in Bowman''s space in both crescentic glomerulonephritis and collapsing glomerulopathy. The pathomechanism and origin of the proliferating cells in these lesions are unknown. In this study, we examined proliferating cells by lineage tracing of either podocytes or parietal epithelial cells (PECs) in the nephrotoxic nephritis model of inflammatory crescentic glomerulonephritis. In addition, we traced the fate of genetically labeled PECs in the Thy-1.1 transgenic mouse model of collapsing glomerulopathy. In both models, cellular bridges composed of PECs were observed between Bowman''s capsule and the glomerular tuft. Genetically labeled PECs also populated larger, more advanced cellular lesions. In these lesions, we detected de novo expression of CD44 in activated PECs. In contrast, we rarely identified genetically labeled podocytes within the cellular lesions of crescentic glomerulonephritis. In conclusion, PECs constitute the majority of cells that compose early extracapillary proliferative lesions in both crescentic glomerulonephritis and collapsing glomerulopathy, suggesting similar pathomechanisms in both diseases.Glomerular epithelial hyperplasia is an important characteristic of crescentic glomerulonephritis (CrGN), also known as rapidly progressive glomerulonephritis. Despite a wide variety of underlying causes, CrGN is characterized commonly by the development of cellular crescents (multilayered accumulation of cells in Bowman''s space) and necrosis of glomerular capillaries.1 Loss of renal function occurs as a consequence of the obstruction of the tubular outlet by cellular crescents, so the proliferating cells present an important target for therapeutic interventions.2Collapsing glomerulopathy (CG) is characterized by massive proteinuria and rapid progressive renal insufficiency and histologically by segmental to global collapse of the capillary tuft and pronounced epithelial cell hyperplasia.3 This pattern has been described in HIV-associated nephropathy,4 parvovirus B19 infection,5 and pamidronate toxicity6 and also as an idiopathic form.3The pathomechanism of the development of cellular lesions remains to be established, and in both CrGN and CG the origin of the hyperplastic cells within cellular lesions has been a matter of debate. In CrGN, the cellular composition of crescents appears to change over time, with predominantly epithelial cells of unknown origin proliferating in early stages and increasing numbers of infiltrating macrophages, lymphocytes, and myofibroblasts in later stages, especially when Bowman''s capsule is ruptured.79 Recent studies also pointed to a contribution of podocytes in the development of crescentic lesions.1013 Collapsing glomerulopathy lesions in turn often are associated with hyperplasia of epithelial cells covering the glomerular tuft, although connections to Bowman''s capsule appeared to be lacking. The visceral localization and the finding that these proliferating cells lacked expression of podocyte markers led to the concept of dysregulated podocytes, which are no longer growth restricted, causing epithelial hyperplasia.14 However, from the findings that these cells expressed markers normally expressed by PECs15 and the finding in serial sections that the cells on the tuft were connected to the PECs on Bowman''s capsule,16 we and others suggested that these cells may originate from parietal epithelial cells (PECs) rather than from podocytes.1620In the studies described above, the origin of the proliferating cells was identified based on the expression or loss of specific markers. This approach may be misleading, given that, first, PECs and podocytes share a common embryonic origin. Only during the last stages of nephrogenesis the phenotypes of both cells diverge. Second, PECs lack specific differentiation markers, and third, proliferating cells may possibly transdifferentiate into cells with a different phenotype. Genetic cell lineage tracing is a technique that has been established recently and enables one to trace cells over prolonged times, even when the cells switch to a different phenotype due to de- or transdifferentiation.19,21 In the present study, we therefore used this technique to trace the relative contributions of PECs and podocytes in the development of cellular glomerular lesions in two murine models of CrGN, namely, nephrotoxic nephritis, and CG, namely, Thy-1.1 transgenic mice. These established murine models were chosen because both characteristically develop proliferative extracapillary lesions.
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